Regulation, Signaling, and Physiological Functions of G-Proteins

Abstract

Heterotrimeric guanine-nucleotide-binding regulatory proteins (G-proteins) mainly relay the information from G-protein-coupled receptors (GPCRs) on the plasma membrane to the inside of cells to regulate various biochemical functions. Depending on the targeted cell types, tissues, and organs, these signals modulate diverse physiological functions. The basic schemes of heterotrimeric G-proteins have been outlined. In this review, we briefly summarize what is known about the regulation, signaling, and physiological functions of G-proteins. We then focus on a few less explored areas such as the regulation of G-proteins by non-GPCRs and the physiological functions of G-proteins that cannot be easily explained by the known G-protein signaling pathways. There are new signaling pathways and physiological functions for G-proteins to be discovered and further interrogated. With the advancements in structural and computational biological techniques, we are closer to having a better understanding of how G-proteins are regulated and of the specificity of G-protein interactions with their regulators.

Keywords: G-protein; GPCR; cellular signaling.

Figure 1

Phylogenetic relationship of human and mouse Gα subunits and their expression.

Figure 2

Phylogenetic relationship of human Gβ subunits and their expression.

Figure 3

Phylogenetic relationship of human Gγ subunits and their expression.

Figure 4

Crystal structures of G-protein heterotrimer. Cartoon diagrams of Gα_i1 (orange) with GDP in space filling representation (color by atom) (a), Gβ₁γ₂ dimer where blue is Gβ, and red is Gγ₂ (b), Gα_i1β₁γ₂ heterotrimer (c), and surface representation of Gα_i1β₁γ₂ heterotrimer (d).

Figure 5

G-protein cycle.

Figure 6

Crystal structure of the complex of β₂-adrenergic receptor and Gs. (a) Cartoon representation of β₂-adrenergic receptor (green) and Gs (orange, blue and red), (b) Close view of the β₂-adrenergic receptor and Gs interface, (c) Surface representation of the β₂-adrenergic receptor and Gs. (d) Superposition of the α subunit of Gs from the apo form (cyan) and from its complex form with β₂-adrenergic receptor (orange).

Figure 7

Crystal structure of the oligomeric β₁-adrenergic receptor in a membrane-like environment. (a) Cartoon representation of β₁-AR as a tetramer in presence of molecular surface highlighting two distinct dimer interfaces. (b) Top view of β₁-AR tetramer down the extracellular surface. (c) Interacting TM1/TM2/H8 and TM4/TM5/ICL2 segments in cartoon diagram in presence of the surface representation of β₁-AR tetramer.

Figure 8

G-protein activation by Ric-8. A GDP-bound Gα subunit disassociates from the membrane and can interact with a GPR-domain containing protein. This complex can then interact with Ric-8, which facilitates the exchange of GTP for GDP. Once activated, Gα can go on to interact with downstream effectors. The signal is terminated when Gα-GTP interacts with a RGS protein, which promotes the hydrolysis of GTP to GDP.

Figure 9

Crystal structure of the complex of Gα_i1 and RGS4. (a) Cartoon representation of Gα_i1 (orange) in complex with RGS4 (magenta). (b) Surface representation of the complex. (c) Cartoon diagram of RGS4.

Figure 10

Crystal structures of Gα in complex with different downstream effectors. (a) Cartoon representation of Gα_s (orange) with adenylyl cyclase (AC) C1A (magenta) and C2A domains (green). (b) Representation of Gα_q (orange) with phospholipase Cβ₃(blue). (c) Representation of Gα_q (orange) with p63RhoGEF (blue) and RhoA (green).

Figure 11

An example of the non-canonical roles of G-protein signaling. In the control of embryonic spindle positioning in C. eiegans fertilized eggs, the Par3/Par6/aPKC complex is localized at the anterior while the Gα and GPR complex is in the posterior (a). The Gα/GPR complex is linked to the spindle through LIN-5 and dynein proteins (b).